Comparative epidemiology of pandemic and seasonal influenza A in households.

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influenza A in households.

Benjamin J Cowling, Kwok Hung Chan, Vicky J Fang, Lincoln L H Lau, Hau Chi So, Rita O P Fung, Edward S K Ma, Alfred S K Kwong, Chi-Wai Chan,

Wendy W S Tsui, et al.

To cite this version:

Benjamin J Cowling, Kwok Hung Chan, Vicky J Fang, Lincoln L H Lau, Hau Chi So, et al.. Com- parative epidemiology of pandemic and seasonal influenza A in households.. New England Journal of Medicine, Massachusetts Medical Society, 2010, 362 (23), pp.2175-84. �10.1056/NEJMoa0911530�.

�pasteur-00588909�

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T h e ne w e ngl a nd jou r na l o f m e dicine

original article

Comparative Epidemiology of Pandemic and Seasonal Influenza A in Households

Benjamin J. Cowling, Ph.D., Kwok Hung Chan, Ph.D., Vicky J. Fang, M.Phil., Lincoln L.H. Lau, B.Sc., Hau Chi So, B.N.S., Rita O.P. Fung, B.N.S., Edward S.K. Ma, M.Phil., Alfred S.K. Kwong, M.B., B.S., Chi-Wai Chan, M.B., B.S.,

Wendy W.S. Tsui, M.B., B.S., Ho-Yin Ngai, M.B., B.S., Daniel W.S. Chu, M.B., B.S., Paco W.Y. Lee, M.B., B.S., Ming-Chee Chiu, M.B., B.S., Gabriel M. Leung, M.D.,

and Joseph S.M. Peiris, D.Phil.

From the Infectious Disease Epidemiolo- gy Group, School of Public Health (B.J.C., V.J.F., L.L.H.L., H.C.S., R.O.P.F., G.M.L.), and the Department of Microbiology (K.H.C., E.S.K.M., J.S.M.P.), Li Ka Shing Faculty of Medicine, University of Hong Kong; Hospital Authority, Government of the Hong Kong Special Administrative Region (A.S.K.K., C.-W.C., W.W.S.T., H.-Y.N., D.W.S.C.); St. Paul’s Hospital (P.W.Y.L.);

St. Teresa’s Hospital (M.-C.C.); and HKU- Pasteur Research Centre (J.S.M.P.) ― all in Hong Kong. Address reprint requests to Dr. Cowling at the School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Units 624-7, Core F Cyberport 3, Pokfulam, Hong Kong, or at bcowling@hku.hk.

Drs. Leung and Peiris contributed equally to this article.

N Engl J Med 2010;362:2175-84.

Abs tr act

Background

There are few data on the comparative epidemiology and virology of the pandemic 2009 influenza A (H1N1) virus and cocirculating seasonal influenza A viruses in com- munity settings.

Methods

We recruited 348 index patients with acute respiratory illness from 14 outpatient clin- ics in Hong Kong in July and August 2009. We then prospectively followed house- hold members of 99 patients who tested positive for influenza A virus on rapid di- agnostic testing. We collected nasal and throat swabs from all household members at three home visits within 7 days for testing by means of quantitative reverse-tran- scriptase–polymerase-chain-reaction (RT-PCR) assay and viral culture. Using hemag- glutination-inhibition and viral-neutralization assays, we tested baseline and con- valescent serum samples from a subgroup of patients for antibody responses to the pandemic and seasonal influenza A viruses.

Results

Secondary attack rates (as confirmed on RT-PCR assay) among household contacts of index patients were similar for the pandemic influenza virus (8%; 95% confidence interval [CI], 3 to 14) and seasonal influenza viruses (9%; 95% CI, 5 to 15). The pat- terns of viral shedding and the course of illness among index patients were also similar for the pandemic and seasonal influenza viruses. In a subgroup of patients for whom baseline and convalescent serum samples were available, 36% of house- hold contacts who had serologic evidence of pandemic influenza virus infection did not shed detectable virus or report illness.

Conclusions

Pandemic 2009 H1N1 virus has characteristics that are broadly similar to those of

seasonal influenza A viruses in terms of rates of viral shedding, clinical illness, and

transmissibility in the household setting.

(3)

H

ouseholds are thought to play a

major role in the community spread of in- fluenza virus during annual epidemics and occasional pandemics.

^1-4

As the pandemic 2009 influenza A (H1N1) virus (hereafter called pandemic virus) spread across the world, many countries implemented mitigation policies, includ- ing the recommendation that persons with con- firmed or suspected infection be isolated at home.

^5-7

The literature contains few data on viral- shedding patterns associated with naturally ac- quired influenza virus infections in community settings. Although data have been published on humoral antibody responses to the pandemic vi- rus after vaccination against seasonal influenza,

⁸

little is known about antibody responses after natu- rally acquired infection or the association of such responses with viral shedding and clinical illness.

We conducted a prospective study of household transmission of influenza A in Hong Kong in July and August 2009. We assessed patterns in viral shedding, course of illness, and transmissibility associated with pandemic and seasonal influenza A virus infection.

Methods

Recruitment and Follow-up of Patients

From 14 outpatient clinics and emergency depart- ments in private hospitals across Hong Kong in July and August 2009, we recruited patients who presented with acute respiratory illness within 48 hours after the onset of illness and who lived with at least two other household members. We used a positive result for influenza A or B on a QuickVue Influenza A+B test (Quidel) to deter- mine the eligibility of index patients and their household contacts for follow-up.

Diaries for recording daily symptoms were pro- vided to all household contacts at an initial home visit, typically within 24 hours after the recruit- ment of the index patient. All household contacts were instructed in a simple hand-hygiene inter- vention

⁹

and provided with liquid hand soap, alcohol hand rub, and a digital tympanic ther- mometer. The period of follow-up for secondary infections in household contacts was approxi- mately 7 days.

Pooled specimens of nasal and throat swabs were collected from all household contacts, re- gardless of whether the person was ill at the ini-

tial home visit, and at two follow-up visits ap- proximately 3 and 6 days later. A subgroup of index patients and household contacts agreed to provide a baseline serum sample at the initial home visit and a convalescent serum sample at the final home visit, after 20 to 35 days.

Written informed consent was obtained from all participants who were 18 years of age or older, and proxy written informed consent for partici- pants under the age of 18 years was obtained from parents or legal guardians. The study proto- col was approved by the institutional review board at the University of Hong Kong.

Laboratory Methods

Nasal and throat swabs were tested by means of a quantitative reverse-transcriptase–polymerase- chain-reaction (RT-PCR) assay to detect the pres- ence of influenza A or B virus and determine molecular viral loads, as described previously.

^9-12

Specimens that were found to be positive were subtyped by means of an RT-PCR assay with the use of subtype-specific primers, and quantitative viral cultures were analyzed to determine the in- fectious viral load in vitro, calculated as the tis- sue-culture infectious dose (TCID

₅₀

), the quantity of virus required for a cytopathic effect in 50% of inoculated cultures.

Serum specimens were tested with a hemagglu- tination-inhibition assay for antibody responses to the pandemic virus A/California/4/2009 and two seasonal influenza viruses: the A/Brisbane/59/

2007 (H1N1) virus and an A/Brisbane/10/2007 (H3N2)–like virus, A/Uruguay/716/2007. Serum specimens were also tested with a viral-neutral- ization assay for antibody responses to the pan- demic virus and the A/Perth/16/2009 (H3N2)–like virus, A/HK/1985/2009. Additional details regard- ing our laboratory methods are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Outcome Measures

We defined serologically confirmed influenza vi-

rus infection as a rise by a factor of four or more

in convalescent serum antibody titers to pandemic

or seasonal influenza A virus, as compared with

titers at baseline. We defined RT-PCR–confirmed

influenza virus infection as a positive result on

testing of one or more nasal and throat specimens

collected during follow-up. We used a broad def-

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epidemiology of Pandemic and Seasonal Influenza A

inition of acute respiratory illness, the presence of at least two signs or symptoms (temperature

≥37.8°C, cough, headache, sore throat, aches or

pains in muscles, runny nose, and phlegm) on 1 or more days during follow-up, which is similar to the definitions used in previous studies.

^9,13

We also used the surveillance definition for influenza-like illness (temperature ≥37.8°C plus cough or sore throat), as recommended by the Centers for Dis- ease Control and Prevention (CDC).

¹⁴

Statistical Analysis

We estimated secondary attack rates, based on the proportion of household contacts in whom influ- enza developed (as determined by RT-PCR assay), as well as rates of acute respiratory illness and influenza-like illness. We calculated 95% confi- dence intervals for the crude secondary attack

rates using a cluster bootstrap method with 1000 resamples.

¹⁵

Households in which one or more household contacts had RT-PCR–confirmed influ- enza at the baseline home visit (i.e., households with one or more potential co-index patients) were excluded from the analysis of secondary attack rates.

We calculated standardized daily scores for three groups of signs and symptoms — systemic signs and symptoms (temperature

≥37.8°C, head-

ache, and myalgia), upper respiratory symptoms (sore throat and runny nose), and lower respira- tory symptoms (cough and phlegm) — by adding up the total number of signs and symptoms that were present and dividing by the highest possible score (3, 2, and 2, respectively).

^16,17

We plotted average symptom scores according to the time since the onset of acute respiratory illness, which

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Figure 1. Enrollment and Outcomes.

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was defined as the first day when the subject re- ported at least two of the seven signs or symptoms listed above.

^16,18

We defined the serial interval as the time be- tween the onset of illness in an index patient and the onset of illness in a household contact. We estimated serial interval distributions on the ba- sis of an underlying Weibull distribution, using methods that have been described previously.

¹⁸

We estimated 95% confidence intervals for the mean serial interval, using a parametric bootstrap ap- proach with 1000 resamples.

^18,19

We estimated geometric mean antibody titers and used Wilcoxon signed-rank tests to compare groups. Antibody titers below the lower limit of 1:10 were estimated to be 1:5 for calculations of geometric mean titers. Statistical analyses were performed with the use of R software, version 2.8.1 (R Development Core Team). Raw data from the study and R syntax to permit additional sta-

tistical analyses are available by contacting the corresponding author.

R esults

Index Patients and Household Contacts

A total of 348 patients consented to participate in the study and met the inclusion criteria. Of these patients, 148 had a positive result on the rapid test. Household contacts of 43 of these patients (29%) declined home visits or could not be con- tacted after numerous repeated attempts. The char- acteristics of these 43 index patients were similar to those of the index patients whom we followed.

The sensitivity of the QuickVue test was 77% (95%

confidence interval [CI], 68 to 85) for seasonal influenza and 80% (95% CI, 70 to 88) for pan- demic influenza, with the results of the RT-PCR assay used as the reference standard. We obtained complete follow-up data for the households of 105 index patients. We excluded the households of six index patients who did not have RT-PCR confirmation of virus infection or who had coin- fection with influenza B or influenza A and B viruses. Thus, we compared the characteristics and transmissibility of pandemic and seasonal influ- enza A viruses in 99 households (Fig. 1).

Oseltamivir was prescribed for 44% of the 99 index patients with pandemic or seasonal influ- enza virus infection (Table 1, and Table 1 in the Supplementary Appendix). Index patients with pandemic infection were on average younger and less likely to have presented with febrile illness than were those with seasonal influenza. The characteristics of household contacts were similar for index patients with pandemic infection and those with seasonal infection.

Secondary Infections

On the basis of RT-PCR results and clinical defi- nitions of infection, secondary attack rates were similar among household contacts of index pa- tients with pandemic influenza A virus infection and those with seasonal infection (Table 2). The attack rates were higher among household con- tacts of index patients who were 15 years of age or younger than among household contacts of older index patients, although the differences were not significant.

On the basis of eight patients with secondary infection and the corresponding index patients, the mean (±SD) serial interval for pandemic virus

Table 1. Characteristics of Index Patients and Their Household Contacts with Pandemic or Seasonal Influenza.

Characteristic Pandemic

Influenza Seasonal

Influenza* P Value†

number (percent) Index patients

No. of patients 45 (100) 54 (100)

Age 0.01

≤5 yr 2 (4) 1 (2)

6–15 yr 20 (44) 19 (35)

16–30 yr 16 (36) 10 (19)

31–50 yr 6 (13) 13 (24)

>50 yr 1 (2) 11 (20)

Male sex 23 (51) 29 (54) 0.96

Oseltamivir prescribed 23 (51) 21 (39) 0.31

Household contacts

No. of patients 130 (100) 154 (100)

Age 0.53

≤5 yr 4 (3) 4 (3)

6–15 yr 18 (14) 31 (20)

16–30 yr 19 (15) 24 (16)

31–50 yr 64 (49) 62 (40)

>50 yr 25 (19) 33 (21)

Male sex 51 (39) 61 (40) 0.95

* Seasonal influenza includes both H1N1 and H3N2 nonpandemic strains of influenza A.

† P values were calculated by means of the chi-square test or Fisher’s exact test.

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infection was estimated at 3.2±1.3 days (95% CI, 2.4 to 4.0). On the basis of seven patients with secondary infection and the corresponding index patients, the mean serial interval for seasonal H3N2 was estimated at 3.4±1.2 days (95% CI, 2.7 to 4.1).

Viral Shedding

Figure 2 shows the rates of viral shedding, accord- ing to RT-PCR assay and culture, and mean stan- dardized symptom scores throughout the course of illness among index patients with pandemic or seasonal influenza A virus infection. For both pandemic and seasonal influenza, molecular vi- ral shedding, as seen on RT-PCR assay, generally ceased after 5 to 7 days of illness. Respiratory symptoms persisted for up to 10 days after the onset of illness. The trends in viral shedding on RT-PCR assay and culture and the course of ill- ness were similar in the subgroup of index pa- tients who did not receive oseltamivir treatment.

Figure 1 in the Supplementary Appendix shows the rates of viral shedding on RT-PCR assay and culture and symptom scores throughout the course of illness in household contacts who had RT-PCR–

confirmed influenza A virus infection. In this small sample, comparisons are imprecise, but on average, infections in household contacts appeared to be associated with lower levels of viral shedding and a shorter duration of clinical illness than in- fections in index patients.

Antibody Titers

Baseline and convalescent serum samples were available for 47 patients with RT-PCR–confirmed pandemic or seasonal influenza A infection. Most of these patients had an increase in antibody ti- ters by a factor of four or more from baseline to convalescence (Fig. 2 in the Supplementary Ap- pendix). The majority of household contacts for whom baseline serum samples were available had low antibody titers against the pandemic or sea-

Table 2. Secondary Attack Rates among Household Contacts of Index Patients with Pandemic or Seasonal Influenza, According to the Age of the Index Patient and the Method of Diagnosis.*

Age of Index Patient

and Method of Diagnosis† Secondary Attack Rate among Household Contacts (95% CI)‡

Pandemic Influenza Seasonal Influenza Any age§

RT-PCR assay 0.08 (0.03–0.14) 0.09 (0.05–0.15)

Acute respiratory illness 0.26 (0.16–0.36) 0.19 (0.12–0.27)

Influenza-like illness 0.06 (0.03–0.11) 0.04 (0.01–0.07)

<16 yr¶

RT-PCR assay 0.11 (0.02–0.23) 0.13 (0.05–0.24)

≥16 yr∥

RT-PCR assay 0.05 (0.00–0.10) 0.07 (0.02–0.12)

* RT-PCR denotes reverse-transcriptase–polymerase chain reaction.

† RT-PCR–confirmed influenza was defined on the basis of a positive RT-PCR assay for one or more pooled nasal and throat swabs. Acute respiratory illness was defined as the presence of at least two of the following symptoms: a temperature of at least 37.8°C, cough, headache, sore throat, myalgia, runny nose, and phlegm. Influenza-like illness was defined as the presence of a temperature of at least 37.8°C plus cough or sore throat.

‡ All 95% confidence intervals were calculated with the use of a cluster bootstrap method.

§ Included in this category were 115 contacts of 41 index patients with pandemic influenza and 148 contacts of 53 index patients with seasonal influenza.

¶ Included in this category were 54 contacts of 19 index patients with pandemic influenza and 61 contacts of 20 index patients with seasonal influenza.

∥ Included in this category were 61 contacts of 22 index patients with pandemic influenza and 87 contacts of 33 index pa- tients with seasonal influenza.

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sonal virus that was associated with the infection in the corresponding index patient (Fig. 3 in the Supplementary Appendix). There was no signifi- cant protective effect of an increased titer of an- tibodies against RT-PCR–confirmed infection.

Of the 19 household contacts who had an in- crease by a factor of four or more in the antibody titer against pandemic (H1N1) or seasonal influ- enza A (H3N2) virus infection, 11 (58%) had de- tectable viral shedding; 10 of these 11 household contacts (91%) reported symptoms of acute re- spiratory illness, whereas only 5 (45%) reported symptoms of influenza-like illness (Table 3). Acute respiratory illness was reported by 27 household contacts for whom paired serum samples were available, but only 12 of these contacts (44%) had serologic evidence of infection or detectable viral shedding on RT-PCR assay (Table 2 in the Sup- plementary Appendix).

Index patients with pandemic influenza who received oseltamivir treatment within 48 hours after the onset of illness had an increase in the geometric mean antibody titer of 4.0 from base- line to convalescence on hemagglutination-inhi- bition assay, whereas patients who did not receive antiviral treatment had a geometric mean titer in- crease of 32.0 (P = 0.03) (Fig. 4 in the Supplemen- tary Appendix). Increases in antibody titers on viral-neutralization assay differed between treat- ed and untreated index patients with pandemic influenza, although the difference was not sig- nificant (P = 0.08). Among index patients with seasonal influenza, there were no significant dif- ferences in titer increases or convalescent anti- body titers between those who received antiviral treatment and those who did not receive such treatment.

Discussion

In this study, the pandemic 2009 H1N1 virus and seasonal influenza A viruses had similar rates of household transmission. However, the observed attack rate for pandemic influenza was higher than that for seasonal influenza, particularly among children. This difference in attack rates could be associated with the lack of preexisting immunity against the pandemic influenza virus

²⁰

rather than an inherent difference in transmis- sibility. Most patients had low levels of immunity to pandemic and seasonal influenza A viruses, as indicated by humoral antibody titers. Pandemic and seasonal influenza A virus infections were

associated with similar patterns of viral shedding and clinical illness.

Secondary attack rates were approximately dou- ble the rates that we observed in the hand-hygiene intervention group of our controlled trial in 2008.

⁹

One possible explanation for this difference is that immunity among household contacts was lower both to pandemic H1N1 virus and to sea- sonal H3N2 virus. The predominant seasonal H3N2 viruses that were circulating in Hong Kong during our study period were antigenically drifted A/Perth/16/2009–like viruses. Secondary attack rates for pandemic and seasonal influenza, as measured by rates of influenza-like illness, were approximately 6% and 4%, respectively, which are slightly lower than secondary attack rates observed in the United States

^4,21

and Kenya

²²

during this pandemic and in previous studies of the transmis- sion of seasonal influenza in households.

^23,24

In our study, the rates of transmission could have differed because of the hand-hygiene intervention that was implemented in all households.

⁹

Second- ary attack rates based on clinical criteria for in- fluenza-like illness were substantially lower than secondary attack rates based on positive results of RT-PCR assay or serologic evidence of infection.

Attack rates based on clinical criteria for acute respiratory illness were higher than rates based on the criteria for influenza-like illness, but the

Figure 2 (facing page). Patterns of Viral Shedding and Course of Illness in Index Patients, According to the Onset of Acute Respiratory Illness.

Panels A and B show the geometric mean viral load on reverse-transcriptase–polymerase-chain-reaction (RT- PCR) assay for index patients with pandemic influenza and those with seasonal influenza, respectively. The lower limit of detection for the RT-PCR assay was approximately 900 copies per milliliter (horizontal lines).

Panels C and D show the geometric mean tissue-culture infectious dose (TCID50) (the quantity of virus required for a cytopathic effect in 50% of inoculated cultures) for index patients with pandemic influenza and those with seasonal influenza, respectively. The lower limit of detection of the quantitative culture assay was approximately 0.3 log10 TCID50 (horizontal lines). Pan- els E and F show the mean scores for lower respiratory, upper respiratory, and systemic symptoms in index patients with pandemic influenza and those with seasonal influenza, respectively. Symptom scores were calculated from a composite of three groups of signs and symptoms of influenza and ranged from 0 to 1, with higher scores indicating a greater severity of symptoms. In all panels, the onset of acute respiratory illness was defined as the self-reported day of illness onset before recruitment to the study.

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incidence of such respiratory illness was poorly correlated with infection confirmed on RT-PCR assay or serologic analysis.

There are few quantitative data on viral-shed-

ding patterns associated with naturally acquired influenza virus infection in community settings, although quantitative data on shedding after in- fection are available from volunteer challenge stud-

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ies

¹⁷

and those involving hospitalized patients.

^25,26

We used a rapid test to screen index patients who sought outpatient care. Since an increased level of viral shedding is associated with increased rapid- test sensitivity,

²⁷

our data on viral shedding and course of illness may represent infections asso- ciated with a generally increased level of viral shedding. The rapid test that we used had mod- erate sensitivity for detecting both pandemic and seasonal influenza strains.

^28,29

The virologic and clinical data on secondary cases should be more representative of naturally acquired influenza vi- rus infections in general than are data on index cases, and these data show that influenza A is as- sociated with mild illness that is often afebrile.

Oseltamivir was prescribed for 44% of outpa- tients who had a positive rapid-test result in our study, which was approximately double the rate among patients with similar characteristics seen in the same clinics in 2007 and 2008.

^9,30

Antivi- ral prophylaxis for close contacts was not pre- scribed during our study period, although it was used during the containment phase earlier in the pandemic.

³¹

Our data suggest that patients with pandemic H1N1 infection may have reduced con-

valescent antibody titers after treatment with os- eltamivir, as compared with no treatment. Fur- ther studies are warranted to confirm or refute this potential association and to investigate the degree to which patients who are infected with 2009 H1N1 virus and are treated with antiviral agents are protected against reinfection in sub- sequent pandemics. A recent report from Chile described three cases of reinfection with 2009 H1N1 virus, and in each case reinfection occurred a few weeks after the first infection was identi- fied and treated with oseltamivir.

³²

In a con- trolled trial involving 374 patients with seasonal influenza virus infection who were randomly as- signed to receive either oseltamivir or placebo, the antibody titer increased from baseline to conva- lescence by a factor of approximately 16 on hemag- glutination-inhibition assay, with no significant difference between the two study groups.

³³

It is possible that a reduced amount of viral antigen is sufficient to elicit a strong antibody response when the patient’s immune system has been primed with a closely related antigen, as is the case in persons who have had previous seasonal influ- enza but not in those with initial exposure to the 2009 pandemic virus. Thus, although the use of oseltamivir may not blunt the antibody response to seasonal influenza, it might do so with pan- demic influenza.

Of 11 household contacts in our study who had detectable viral shedding on RT-PCR assay, only 1 did not report the occurrence of acute respira- tory illness, although 6 of the 11 contacts did not report the occurrence of influenza-like illness.

Some household contacts who had serologic evi- dence of infection with pandemic or seasonal influenza did not have viral shedding and did not report illness, and the presence of viral shedding was closely correlated with illness. Viral shedding before the onset of acute respiratory illness was rare in household contacts who had RT-PCR–con- firmed influenza virus infection.

Our study had a number of limitations. First, we used a case-ascertainment study design in which index patients were recruited from outpa- tient clinics,

^9,34,35

and we used a rapid test to screen these patients for influenza virus infec- tion. Such recruitment leads to bias in the selec- tion of index patients, although secondary cases among household contacts should be representa- tive of influenza A virus infections in the com- munity. The index patients in our study had ill-

Table 3. Presence of Viral Shedding and Clinical Illness among 19 Household Contacts with Serologic Evidence of Pandemic or Seasonal Influenza.*

Variable Increase in Antibody Titer†

Pandemic Influenza

(N = 11) Seasonal Influenza (N = 8) no. (%)

Viral shedding detected on

RT-PCR assay 7 (64) 4 (50)

Temperature ≥37.8°C 3 (27) 3 (38)

Cough 6 (55) 6 (75)

Acute respiratory illness‡ 6 (55) 6 (75)

Influenza-like illness‡ 3 (27) 2 (25)

* This analysis was based on the subgroup of 94 household contacts for whom serum samples were obtained during the acute and convalescent phases of illness: 54 contacts of index patients with pandemic influenza and 40 contacts of index patients with seasonal influenza. RT-PCR denotes reverse-transcriptase–polymerase chain reaction.

† An increased antibody titer was defined as an increase by a factor of four or more. Analyses were performed with the use of viral neutralization to A/

California/4/2009 (H1N1) (for index patients with RT-PCR–confirmed pandemic influenza) or A/Perth/16/09 (H3N2)–like virus A/HK/1985/2009 (for contacts of index patients with RT-PCR–confirmed seasonal influenza).

‡ Acute respiratory illness was defined as the presence of at least two of the following symptoms: a temperature of at least 37.8°C, cough, headache, sore throat, myalgia, runny nose, and phlegm. Influenza-like illness was defined as the presence of a temperature of at least 37.8°C plus cough or sore throat.

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ness that was severe enough to warrant medical attention and had a positive result on a rapid test.

If more severe illness or a higher level of viral shedding in association with a positive rapid-test result

²⁷

reflects greater infectiousness, we may have overestimated household secondary attack rates in the general community. Second, the hand- hygiene intervention that was provided to all households may have reduced the rate of trans- mission,

⁹

perhaps to a similar extent for pandemic and seasonal viruses. Finally, we collected nose and throat swabs during home visits at 3-day in- tervals, and we may have missed some RT-PCR–

positive infections if peak viral shedding in the respiratory tract occurred between these visits.

We may also have missed secondary infections that occurred more than 7 days after the recruit- ment of index patients.

In spite of the differences in the age groups affected and occasional complications in patients with underlying disease, most of the epidemio- logic data from affected countries suggest that pandemic 2009 H1N1 virus infection is not, on

average, a more severe illness than seasonal in- fluenza. Experimental data from in vitro cultures of primary human cells and ex vivo cultures of human respiratory tissue suggest that viral tro- pism and replication kinetics are similar for pan- demic and seasonal H1N1 viruses.

³⁶

However, data from animal models suggest that the 2009 H1N1 virus causes more severe illness and may be less transmissible than seasonal influenza vi- ruses.

^37,38

Our study suggests that pandemic and seasonal influenza A viruses are associated with similar viral-load dynamics, severity of clinical ill- ness, and transmissibility.

Supported by grants from the National Institute of Allergy and Infectious Diseases (HHS-N266200700005C and N01- AI-70005) and the Hong Kong University Grants Committee (AoE/M-12/06).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank all the doctors, nurses, and staff members at the participating centers for facilitating recruitment; the dedicated team of health care workers who conducted the home visits; and Chan Kit Man, Calvin Cheng, Lai-Ming Ho, Ho Yuk Ling, Dennis Ip, Lam Yiu Pong, Max Lau, Tom Lui, Tong Hok Leung, Alfred Yeung, Eileen Yeung, Jenny Yuen, and Zhou Ying for research support.

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